Process for the preparation of tetrasubstituted imidazole derivatives and novel crystalline structures thereof

ABSTRACT

The present invention relates to a process for preparing tetrasubstituted imidazole derivatives of the general formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , R 3  and R 4  are as defined in the specification below. 
           
         
       
    
     The present invention further relates to a process for preparing the compound of formula (II) 
     
       
         
         
             
             
         
       
         
         
           
             and novel crystalline structures of the compound of formula (II).

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional application Ser.No. 60/278,607, filed Mar. 26, 2001, the contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a process for preparingtetrasubstituted imidazole derivatives of the general formula (I)

wherein R¹, R², R³ and R⁴ are as defined in the specification below.

The present invention further relates to a process for preparing thecompound of formula (II)

and novel crystalline structures of the compound of formula (II).

BACKGROUND OF THE INVENTION

The invention relates to a process for preparing tetrasubstitutedimidazole derivatives represented by the formula (I)

wherein R¹, R², R³ and R⁴ are as defined in the specification below.

The compounds of formula (I) inhibit the in vitro activity of p38 in thenanomolar range. In addition, the compounds inhibit the in vitrosecretion of tumor necrosis factor α (TNF-α) and IL-β in the nanomolarrange. Animal models demonstrate the inhibition of LPS induces TNF-α, aswell as the inhibition of rheumatoid arthritis. The compounds of formula(I) are useful in the treatment of a variety of cytokine relateddisorders including rheumatoid arthritis, inflammatory bowel disease,septic shock, osteoporosis, osteoarthritis, neuropathic pain, HIVreplication, HIV dementia, viral myocarditis, insulin-dependentdiabetes, non-insulin dependent diabetes, periodontal disease,restenosis, alopecia areta, T-cell depletion in HIV infection or AIDS,psoriasis, acute pancreatitis, allograft rejection, allergicinflammation in the lung, atherosclerosis, multiple sclerosis, cachexia,Alzheimer's disease, stroke, Crohn's disease, ischemia, congestive heartfailure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-BarreSyndrome and systemic lupus erythematosus. (U.S. Pat. No. 5,965,583Issued Oct. 12, 1999)

The current invention relates to an efficient process for preparingcompounds of formula (I). In a further aspect, the present inventionrelates to a process for preparing the compound of formula (II).

The compound of formula (II) is an orally active inhibitor of p38kinase. p38 kinase inhibitors have utility in suppressing the release ofTNF-α from monocytes and would be expected to suppress signaltransduction initiated by this proinflammatory mediator. Thus p38 kinaseinhibitors have utility in the treatment of various inflammatory andautoimmune disorders such as rheumatoid arthritis, sepsis, inflammatorybowel disease, acute respiratory distress syndrome, as well as cachexiaand bone resorption (osteoporosis and osteoarthritis).

The present invention further relates to novel crystalline structures ofthe compound of formula (II), more specifically Form A and Form B.

A process for synthesizing pyridyl imidazole compounds is disclosed inU.S. Pat. No. 5,670,527, issued Sep. 23, 1997 (Adams, J. L., et. al.,SmithKline Beecham Corp. Assignee) and in PCT application WO 96/21452,published Jul., 18, 1996 (Adams, J. L., et. al., SmithKline BeechamCorporation).

U.S. Pat. No. 5,965,583 (Issued Oct. 12, 1999), which is incorporatedherein by reference, disclose a process for preparing the compounds offormula (I). This process requires chromatographic separation ofintermediates, making it unsuitable for large scale production.

Thus there exists a need for a process which is compatible with largescale production needs and which achieves acceptable levels of purityand yield.

BRIEF SUMMARY OF THE INVENTION

The invention relates to a process for preparing a compound of formula(I):

wherein

R¹ is selected from the group consisting of phenyl, substituted phenyl,(where the substituents are selected from C₁–C₅alkyl, halogen ortrifluoromethyl) and heteroaryl, where the heteroaryl contains 5 to 6ring atoms;

R² is selected from the group consisting of phenyl, substituted phenyl,(where the substituents are selected from C₁–C₅alkyl, halogen ortrifluoromethyl) and heteroaryl, where the heteroaryl contains 5 to 6ring atoms and is optionally C₁–C₄alkyl substituted;

R³ is selected from the group consisting of hydrogen, arylC₁–C₅alkyl,substituted arylC₁–C₅alkyl, (where the aryl substituents areindependently selected from one or more of C₁–C₅alkyl, C₁–C₅alkoxy,halogen, amino, C₁–C₅alkylamino or di(C₁–C₅alkyl)amino),phthalimidoC₁–C₅alkyl, succinimidoC₁–C₅alkyl,C₁–C₅alkylcarbonylC₁–C₅alkyl, aryloxycarbonylC₁–C₅alkyl, andheteroarylC₁–C₅akyl, where the heteroaryl contains 5 to 6 ring atoms;

R⁴ is

where

p is an integer from 0 to 9;

X is selected from the group consisting of hydrogen, hydroxy, vinyl,substituted vinyl, (where one or more substituents are selected fromfluorine or chlorine), ethynyl, substituted ethynyl (where thesubstituent is selected from fluorine or chlorine), C₁–C₅alkyl,substituted C₁–C₅alkyl (where the alkyl substituents are selected fromone or more of C₁–C₅alkoxy, trihaloalkyl, phthalamido or amino),C₃–C₇cycloalkyl, C₁–C₅alkoxy, substituted C₁–C₅alkoxy (where the alkylsubstituents are selected from phthalimido or amino), phthalimidooxy,phenoxy, substituted phenoxy (where the phenyl substituents are selectedfrom C₁–C₅alkyl, fluorine, chlorine or C₁–C₅alkoxy), phenyl, substitutedphenyl (where the phenyl substituents are selected from C₁–C₅alkyl,fluorine, chlorine or C₁–C₅alkoxy), arylC₁–C₅alkyl, substitutedarylC₁–C₅alkyl (where the aryl substituents are selected fromC₁–C₅alkyl, fluorine, chlorine or C₁–C₅alkoxy),arylhydroxyC₁–C₅alkylamino, C₁–C₅alkylamino, di(C₁–C₅alkyl)amino,nitrile, oxime, benzyloxyimino, C₁–C₅alkyloxyamino, phthalimido,succinimido, C₁–C₅alkylcarbonyloxy, phenylcarbonyloxy, substitutedphenylcarbonyloxy (where the phenyl substituents are selected fromC₁–C₅alkyl, fluorine, chlorine or C₁–C₅alkoxy),phenylC₁–C₅alkylcarbonyloxy, (where the phenyl substituents are selectedfrom C₁–C₅alkyl, fluorine, chlorine or C₁–C₅alkoxy), aminocarbonyloxy,C₁–C₅alkylaminocarbonyloxy, di(C₁–C₅alkyl)aminocarbonyloxy,C₁–C₅alkoxycarbonyloxy, substituted C₁–C₅alkoxycarbonyloxy (where thealkyl substituents are selected from the group consisting of methyl,ethyl, isopropyl and hexyl), phenoxycarbonyloxy, substitutedphenoxycarbonyloxy (where the phenyl substituents are selected fromC₁–C₅alkyl, fluorine, chlorine or C₁–C₅alkoxy), C₁–C₅alkylthio,substituted C₁–C₅alkylthio (where the alkyl substituents are selectedfrom hydroxy and phthalimido), C₁–C₅alkylsulfonyl, phenylsulfonyl andsubstituted phenylsulfonyl (where the phenyl substituents are selectedfrom fluorine, chlorine, C₁–C₅alkoxy or trifluoromethyl);

or pharmaceutically acceptable salts thereof;

comprising

reacting an aldehyde of formula (III) to produce the correspondingcompound of formula (IV), where L¹ and L² are independently selectedfrom the group consisting of C₁–C₄alkyl and C₁–C₄aralkyl; or L¹ togetherwith L² is selected from the group consisting of —CH₂—CH₂— (optionallysubstituted with one to four C₁–C₃ alkyl), and —CH₂—CH₂—CH₂— (optionallysubstituted with one to six C₁–C₃ alkyl);

in a separate reaction vessel, reacting an aldehyde of formula (V), withan alkali metal salt of bis(trimethylsilyl)amide, to produce thecorresponding trimethylsilyl substituted imine of formula (VI);

reacting the compound of formula (IV) with an alkyl lithium to producethe corresponding lithium intermediate of formula (VII);

reacting the lithium intermediate of formula (VII) with thetrimethylsilyl substituted imine of formula (VI) to produce thecorresponding compound of formula (VIII);

in a separate vessel, reacting a substituted amine of formula (IX) withN,N′-carbonyldiimidazole, to yield the corresponding compound of formula(X);

reacting the compound of formula (VIII) with the compound of formula(X), to produce the corresponding compound of formula (XI);

cyclizing the compound of formula (XI), under acid conditions of pH lessthan about 7, to produce the corresponding compound of formula (XII);

reacting the compound of formula (XII) with POBr₃, PBr₅, or in a mixtureof PBr₃ and Br₂, to yield the corresponding compound of formula (XIII);

displacing the bromine on the compound of formula (XIII) by reactingwith a compound of formula (XIV), to produce the corresponding compoundof formula (I).

In another aspect, the present invention relates to a process forpreparing the compound of formula (II).

In a further aspect, the present invention is directed to intermediatesof formula (XI) and formula (XII), and a process for preparing same. Instill another aspect of the present invention is a process for preparingthe intermediate compound of formula (XIII).

In a further aspect, the present invention is directed to novelcrystalline structures of the compound of formula (II), wherein thecrystalline forms are herein referred to as Form A and Form B, which maybe characterized by their respective X-ray powder diffraction patterns.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, includes straight, branched and cyclic chain alkylgroups. For example, alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote a group ofthe formula —O-(alkyl), for example, methoxy, ethoxy, n-propoxy,sec-butoxy, t-butoxy, n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted mono and fused aromatic rings such as phenyl, naphthyl,and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from sulfur, oxygen and nitrogen. In thecase of five-membered rings, the heteroaryl will contain one sulfur,oxygen or nitrogen atoms and, in addition, may contain up to threeadditional nitrogen atoms. In the case of six-membered rings, theheteroaryl may contain up to three nitrogen atoms. Examples of suchheteroaryls include, but are not limited to, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, pyrimidi-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl,thiophen-3-yl, pyridazinyl, triazinyl, thiazolyl, oxazolyl, pyrazolyl,and the like.

As used herein, unless otherwise noted, “aralkyl” shall mean any C₁–C₅alkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. For example, benzyl, phenylethyl, and the like.

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, the term “alkali metal” shall refer to a Group I metalcation such as lithium, sodium, potassium and cesium cations.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

During any of the processes of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, John Wiley & Sons, 1991. The protecting groups may be removedat a convenient subsequent stage using methods known from the art.

The invention relates to a process for preparing compounds of formula(I) as more fully described in Scheme 1.

As set forth in Scheme 1 above, an aldehyde of formula (III), a knowncompound or compound prepared by known methods, is reacted with analcohol, diol or trialkoxymethane, preferably trimethoxymethane,preferably in the presence of methanol, in a solvent capable ofazeotropic removal of water such as benzene, toluene, xylene, and thelike, in the presence of an acid such as sulfuric acid,p-toluenesulfonic acid, and the like, preferably sulfuric acid, atreflux temperature, to produce the corresponding compound of formula(IV). (Sheldrake, P. W., Synth Commun. (1993) 23(14), 1967–71)

In a separate reaction vessel, an aldehyde of formula (V), a knowncompound or compound prepared by known methods, is reacted with analkali metal salt of bis(trimethylsilyl)amide, preferably lithiumbis(trimethylsilyl)amide, in an organic solvent such as tetrahydrofuran(THF), diethyl ether, t-butylmethylether (MTBE), and the like,preferably THF, at a temperature in the range of about −20° C. to aboutroom temperature, preferably at a temperature of about 0° C., to producethe corresponding trimethylsilyl (TMS) substituted imine of formula(VI). (Ojima, I., et. al., Tetrahedron (1996), 52, 209–224)

The compound of formula (IV) is reacted with an alkyl lithium such asmethyl lithium, ethyl lithium, n-butyl lithium, and the like, preferablyn-butyl lithium, at a temperature which prevents decomposition of thelithium intermediate of formula (VII), preferably at a temperature ofless than or equal to about −20° C., in an organic solvent such astetrahydrofuran (THF), diethylether, t-butylmethylether (MTBE), and thelike, preferably THF, to produce the corresponding lithium intermediateof formula (VII).

The lithium intermediate of formula (VII) is reacted with the TMSsubstituted imine of formula (VI) in the presence of an organic solventsuch as tetrahydrofuran (THF), diethylether, t-butylmethylether (MTBE),and the like, preferably THF, preferably allowing warming of thereaction mixture to about room temperature, to produce the correspondingcompound of formula (VIII).

In a separate reaction vessel, a substituted amine of formula (IX), aknown compound or compound prepared by known methods, is reacted withN,N′-carbonyldiimidazole, a known compound, in an inert organic solvent,such as tetrahydrofuran (THF), diethylether, t-butylmethylether (MTBE),toluene, dichloromethane (DCM), and the like, preferably THF, preferablyat room temperature, to produce the corresponding compound of formula(X).

The compound of formula (VIII) is reacted with the compound of formula(X), in an organic solvent such as toluene, tetrahydrofuran (THF),dimethylformamide (DMF), and the like, preferably toluene, at atemperature in the range of about 50–150° C., preferably for toluene, atabout reflux temperature, to produce the corresponding compound offormula (XI).

The compound of formula (XI) is cyclized in an acid such as formic acid,aqueous hydrochloric acid, and the like, preferably aqueous hydrochloricacid, preferably at a temperature in the range of about 80–150° C., mostpreferably at a temperature in the range of about 95–100° C., to yieldthe corresponding compound of formula (XII).

The compound of formula (XII) is reacted with phosphorus oxybromide(POBr₃) or phosphorous pentabromide (PBr₅), preferably POBr₃, in anamount equal to at least about 5 equivalents, in an inert organicsolvent whose boiling point is greater than or equal to about 110° C.,such as tetramethylenesulfone, xylene, toluene, and the like, preferablytetramethylenesulfone, preferably in an amount equal to about 2 weightequivalents, at a temperature of greater than or equal to about 110° C.,preferably at a temperature of about 130° C., to yield the correspondingcompound of formula (XIII).

Alternatively, the compound of formula (XII) is reacted with a mixtureof PBr₃ and Br₂ (which produces PBr₅ in situ), wherein the ratio of PBr₃to Br₂ is in the range of about 1:2 to about 2:1, preferably the ratioof PBr₃ to Br₂ is about 1:1; wherein the amount of the PBr₅ produced bythe mixture of PBr₃ and Br₂ is in the range of about 3–3.5 equivalents;in a solvent such as POCl₃ or in an inert organic solvent whose boilingpoint is greater than or equal to about 110° C., such astetramethylenesulfone (sulfolane), xylene, toluene, and the like,preferably POCl₃; at a temperature in the range of about 10–45° C.,preferably at a temperature in the range of about 20–35° C.; to yieldthe corresponding compound of formula (XIII).

The bromine on the compound of formula (XIII) is displaced by reactingwith a compound of formula (XIV), a known compound or compound preparedby known methods, in the presence of a Pd(II) catalyst such asdiacetoxybis (triphenylphosphine) palladium (Pd(OAc)₂(Ph₃P)₂,), dichlorobis(triphenylphosphine) palladium (PdCl₂(Ph₃P)₂), and the like, or inthe presence of a catalyst such as palladium acetate (Pd(OAc)₂) orpalladium chloride (PdCl₂), wherein the palladium acetate or palladiumchloride catalyst is further in the presence of triphenylphosphine,preferably the catalyst is diacetoxybis (triphenylphosphine) palladium,preferably in the presence of a co-catalyst such as copper(I) iodide(CuI), Fe powder, and the like, preferably CuI, in the presence of anorganic amine such as diisopropylamine, diisopropylethylamine (DIPEA),triethylamine (TEA), piperidine, and the like, or an inorganic base suchas K₂CO₃, Cs₂CO₃, and the like, preferably an organic amine, morepreferably diisopropylamine, optionally in an inert organic solvent suchas THF, t-butyl methyl ether (MTBE), diethyl ether, DMF, acetonitrile,and the like, with heating to a temperature in the range of about60–100° C., preferably to a temperature of about 75° C., to produce thecorresponding compound of formula (I).

Alternatively, the compound of formula (XI) may be prepared according tothe process outlined in Scheme 2

wherein L¹, L², R¹, R² and R³ are as set forth above.

More particularly, the compound of formula (VIII) is reacted with acompound of formula (XV), in an inert organic solvent such astetrahydrofuran (THF), dimethylformamide (DMF), toluene, and the like,preferably THF, preferably at room temperature, to produce thecorresponding compound of formula (XI).

In a preferred embodiment of the invention, the process is used toprepare the compound of formula (II). Preferably, the compound offormula (II) is further purified by known methods such asrecrystallization from an organic solvent such as toluene, methanol,acetone, acetonitrile, and the like or from a mixture of organicsolvents such as ethyl acetate/hexane, THF/toluene, ethylacetate/toluene, and the like.

The present invention is further directed to novel crystallinestructures of the compound of formula (II). The crystalline forms of thecompound of formula (II) may be prepared by recrystallization of thecompound of formula (II) from a suitable organic solvent such asacetone, acetonitrile, THF/toluene mixture, and the like.

Recrystallization of the compound of formula (II) as described abovewill yield one of two novel crystalline forms, herein referred to asForm A and Form B. Form B is obtained by recrystallization from acetoneor a mixture of THF:toluene, more preferably a 1:2 mixture ofTHF:toluene. Form A is obtained by recrystallization from acetonitrile.

The novel crystalline forms of the compound of formula (II) may becharacterized by their respective x-ray powder diffraction patternsutilizing a Siemens D5000T-T based powder diffractometer using CuK_(α)radiation and the following system conditions:

-   -   a) CuKα radiation, 35 mA, 40 KV    -   b) Optics        -   1 mm slit, Gobel mirrors, 0.6 mm slit, & vertical soller            slits between tube and sample        -   LiF monochromator between sample and detector    -   c) Scan 5 to 35°2θ at 0.02 Step Size at a rate of 1°2θ/minute    -   d) TTK-450 variable temperature/humidity stage and holder

Form A of the compound of formula (II) may be characterized by its X-raydiffraction pattern, which comprises the major peaks as listed in Table1.

TABLE 1 FORM A POWDER X-RAY DIFFRACTION PEAKS Relative ANGLE 2θd-Spacing (Å) Intensity (%) 6.599 13.384 15.2 7.817 11.300 14.4 11.6767.573 33.2 17.536 5.053 11.6 18.428 4.811 38.3 19.318 4.591 19.9 19.9484.447 100.0 20.852 4.256 10.1 21.463 4.137 43.3 23.260 3.821 39.5 23.8833.723 80.6 24.804 3.587 57.9 25.119 3.542 31.9 25.579 3.480 12.3 26.2513.392 21.5 26.725 3.333 58.6 28.229 3.159 11.4 30.487 2.9296 23.0 31.6142.8278 17.6

Form B of the compound of formula (II) may be characterized by its X-raydiffraction pattern, which comprises the major peaks as listed in Table2.

TABLE 2 FORM B POWDER X-RAY DIFFRACTION PEAKS Relative ANGLE °2θd-Spacing (Å) Intensity (%) 7.206 12.257 100.0 8.961 9.861 14.2 10.6178.326 24.8 12.438 7.110 14.0 15.500 5.712 33.7 16.458 5.382 13.3 17.3605.104 17.2 17.879 4.957 37.6 18.343 4.833 19.2 18.665 4.750 31.8 19.1264.637 16.1 19.943 4.448 21.9 20.491 4.331 30.8 21.469 4.135 52.9 21.8914.057 59.8 22.371 3.971 58.7 22.778 3.901 12.0 23.159 3.837 51.0 23.8703.725 20.8 24.526 3.627 15.5 24.704 3.601 25.9 25.113 3.543 14.7 26.3683.377 11.0 27.674 3.221 10.5 28.088 3.174 18.3 28.896 3.087 21.3 29.2913.047 19.4 30.201 2.9568 10.6 30.501 2.9284 13.3

The following examples describe the invention in greater detail and areintended to illustrate the invention, but not to limit it.

EXAMPLE 1 4-(Dimethoxymethyl)pyridine

To a solution of 4-pyridinecarboxaldehyde (100.00 g, 0.93 mol) andtrimethylorthoformate (159.20 g, 1.50 mol) in methanol (180 mL) at 0°C., under N₂ was added concentrated sulfuric acid (41 mL, 0.45 mol). Theresulting white suspension was heated to reflux and stirred for 24hours. The reaction solution became clear after 2 h. After cooling toroom temperature, the reaction mixture was poured slowly into a solutionof 25 wt. % sodium methoxide (360 mL) in methanol (300 mL). The mixturewas then concentrated in vacuo to a light brown thick oil. To this crudeoil was added t-butylmethyl ether (500 mL), followed by the slowaddition of water (40 mL) (to convert the inorganics to filterablesolids). After filtration through a pad of Celite, the filtrate wasconcentrated to yield a light brown oil. The crude oil was vacuumdistilled to yield the desired product as a colorless oil

Yield: 88.91 g (62.4%)

BP 69–71° C. at 1 mm Hg

EXAMPLE 2 2,2-Dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine

Step A:

To a stirred solution of 1M lithium bis(trimethylsilyl)amide in THF (300mL, 0.30 mol), under N₂, was added 4-fluorobenzaldehyde (37.23 g, 0.30mol), dropwise at 0° C. The resulting mixture was stirred at roomtemperature for 30 min to yield a solution.

Step B:

In a second flask, 4-dimethoxymethylpyridine (38.29 g, 0.25 mol) wasmixed with THF (200 mL) and cooled to −20° C. To the solution was slowlyadded dropwise 2.5M n-butyl lithium in hexane (120 mL, 0.30 mol), withthe temperature of the reaction solution maintained between −15 and −20°C. The resulting dark brown reaction mixture was stirred at −20° C. for15 min. To the reaction mixture was slowly added the solution from stepA above. The temperature of the reaction solution was maintained below−15° C. After addition, the dark brown reaction mixture was stirred andwarmed up to room temperature. The reaction mixture was quenched with 2Naqueous HCl (500 mL) to a pH of about 2.0, and the resulting layers wereseparated. The organic layer was extracted once with 1N aqueous HCl (100mL). The combined aqueous layers were washed with ethyl acetate (2×150mL) and then basified with addition of 50% aq. NaOH solution, to a pH ofabout 10. The basified mixture was extracted with ethyl acetate (400 mL,2×100 mL). The combined ethyl acetate extracts were washed with water(200 mL), brine (200 mL), and dried with Na₂SO₄. After concentration invacuo, the crude product was obtained as a thick brown oil.

Yield: 54.70 g (79%)

EXAMPLE 3 N-(3-phenylpropyl)-1H-imidazole-1-carboxamide

To a suspension of 1,1′-carbonyldiimidazole (33.00 g, 0.203 mol) in THF(100 mL) at room temperature under N₂, was added 3-phenylpropylamine(25.00 g, 0.185 mol) in THF (50 mL), dropwise. The reaction mixturebecame clear during the addition of the 3-phenylpropylamine. Aftercompletion of the addition, the clear solution was stirred for 30 min atroom temperature and then quenched with water (150 mL) and ethyl acetate(200 mL). The layers were separated and the organic layer washed withwater (150 mL), brine (150 mL), and dried with Na₂SO₄. The solvents wereremoved in vacuo to yield a white wax-like solid.

Yield: 47.50 g

EXAMPLE 4N-(3-phenylpropyl)-N′-[(2.2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethyl)]urea

A solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4fluorophenyl)ethanamine(51.12 g, 0.185 mol) and N-(3-phenylpropyl)-1H-imidazole-1-carboxamide(42.42 g, 0.185 mol) in toluene (300 mL) under N₂, was stirred andheated to reflux temperature for 3 h. The solution was cooled to roomtemperature and the dark brown solution was diluted with ethyl acetate(200 mL). The mixture was washed with water (2×200 mL), brine (200 mL),and dried with Na₂SO₄. The solvents were removed in vacuo to yield abrown solid which was recrystallized from a solvent mixture of ethylacetate/hexane (1:1) to yield an off-white solid.

Yield: 38.00 g (47%)

EXAMPLE 51,3-dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-2H-imidazlin-2-One

N-(3-phenylpropyl)-N′-[(2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethyl)]urea (38.0 g, 86.8 mmol) was dissolved in formic acid (100 mL) to form abrown solution. The solution was heated to 95–100° C. and stirred underN₂ for 24 h. The solution was then cooled to room temperature, theformic acid was removed under reduced pressure by rotoevaporator and theresidue diluted with ethyl acetate (300 mL). The solution was basifiedwith 6N NaOH to a pH of about 10. An off-white solid formed slowly inthe organic layer. The clear aqueous layer was separated and extractedwith ethyl acetate (50 mL). The combined organic layers were dilutedwith t-butylmethylether (350 mL) and stirred for 30 min. The solidproduct was collected by filtration, washed with t-butylmethyl ether(100 mL) and air-dried for 1 h. The solid product was dried in a vacuumoven at room temperature for 24 h to yield the product as an off-whitesolid.

Yield: 18.11 g (58%) MP: 198–199.5° C.

EXAMPLE 62-bromo-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazoleHBr salt

1,3-dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-2H-imidazolin-2-one(5.0 g, 13.4 mmol) was suspended in sulfolane (20.0 g,) and treated withPOBr₃ (19.5 g, 68 mmol). The mixture was heated to 130° C. and stirredunder N₂ for 3–3.5 h. The reaction solution was cooled to roomtemperature, diluted with t-butylmethyl ether (100 mL) and cooledfurther to 0° C. The reaction mixture was quenched slowly with 10% NaOHsolution (120 mL) to a pH of about 10. The layers were separated and theaqueous layer was extracted with t-butylmethyl ether (30×2 mL). Thecombined organic layers were washed with water (50×2 mL), brine (50 mL),and dried with Na₂SO₄. The solvent was removed in vacuo and the residuedissolved in a mixture of ethyl acetate (100 mL) and methanol (5 mL).The solution was treated with 2.88M HBr solution in ethyl acetate (9.3mL, 26.8 mmol). The resulting yellow suspension was warmed on asteam-bath. Methanol (5 mL) was added to the suspension, resulting inthe formation of a solution, and the solution was stirred overnight atroom temperature (ca. 18 h). Ethyl acetate (50 mL) was then added slowlyand the suspension was stirred for another 1 h. The precipitate wascollected by filtration and washed with ethyl acetate (50 mL). The solidwas dried in a vacuum oven at room temperature for 2 h, to yield theproduct as a yellowish solid.

Yield: 5.01 g (62%), MP: 214–216° C., (color change at 205° C.)

EXAMPLE 74-(4-fluorophenyl)-2-(4-hydroxy-1-butynyl)-1-(3-phenylpropyl)-5-(4-pyridyl)imidazole

To a stirred solution of4-(4-fluorophenyl)-2-iodo-1-(3-phenylpropyl)-5-(4-pyridyl)imidazole(1.42 g, 2.74 mmol) and 3-butyn-1-ol (0.289 g, 4.1 mmol) indiisopropylamine (10 mL) was added bis(acetato)-bis(triphenylphosphine)palladium (0.102 g, 0.14 mmol), followed by the addition of copper(I)iodide (0.052 g, 0.274 mmol). The mixture was stirred at 75° C. for 4 h.The reaction mixture was then cooled to room temperature and quenchedwith water (100 mL). The mixture was extracted with ethyl acetate (2×50mL). The combined ethyl acetate extract was washed with water (2×30 mL),brine (30 mL), and dried with Na₂SO₄. After removal of solvents, thecrude product was obtained as a brown solid.

The crude product was purified by recrystallization from a mixture ofethyl acetate/hexane to yield the product as a yellow solid.

Yield: 0.88 g (75%) MP: 121–122° C.

EXAMPLE 81,3-dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-2H-imidazol-2-one

N-(3-phenylpropyl)-N′-[(2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethyl)]urea (224 g, 0.45 mol) was mixed with 4N HCl (800 g) and heated underreflux for 4-5 h (95–100° C.). Upon completion, the reaction was cooledto room temperature and adjusted to pH 13 with 8N NaOH solution (480 g),resulting in precipitation of a solid product. The pH of the suspensionwas controlled to pH≧13 for 30 min, with addition of sodium hydroxide asneeded. The suspension was centrifuged and the aqueous phase removed anddiscarded. The solid was resuspended in 2N NaOH solution (1000 g),centrifuged a second time and then re-suspended in water (2×1000 g,water phase pH 7). The solid product was dried at 45–50° C., undervacuum (for about 4–5 days), to a final water content of <2%, to yieldthe product as a tan solid.

Yield: 175 g

EXAMPLE 94-(4-fluorophenyl)-2-bromo-1-(3-phenylpropyl)-5-(4pyridyl)-imidazole

1,3-Dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5(4-pyridyl)-2H-imidazol-2-one(100 g, 0.26 mol) was mixed with POBr₃ (268.7 g, 0.93 mol) and sulfolane(200 g) and the reaction mixture was heated to a temperature of 120–125°C. for 1–2 h. Upon completion, the reaction mixture was cooled to 40° C.Cautiously, over about 30 min, 2N NaOH solution (53 g) was added.Additional 2N NaOH solution (53 g) was then added at faster rate. Thereaction mixture was then cooled to 15–20° C. and 4N NaOH solution (802g) was added to adjust the solution to pH 7–8. The aqueous phase wasextracted with t-butylmethyl ether (3×143 g) and the organic phasescombined. To the combined organic phase was added t-butylmethyl ether(107 g). The solution was washed with water (2×150 g), resulting in theprecipitation of a solid, which was collected by filtration.

HBr Salt:

A solvent exchange solution of t-butylmethyl ether to ethyl acetate wasused for the crystallization of the HBr salt.

The t-butylmethyl ether phase was concentrated to 150 g (about ½volume), diluted with ethyl acetate (460 g) and concentrated again to160 g. The resulting oil was dissolved in ethyl acetate (460 g), HBr gas(21 g, 0.26 mol) was introduced and the solution heated to reflux,resulting in a separate yellow oil layer. Methanol (80 g) was added tothe boiling mixture (65° C.), resulting in formation of a solid. Thesolution was stirred and cooled to 20–25° C. over about 4 h. The mixturewas stirred overnight and cooled to 5° C. Ethyl acetate (160 g) was thenadded to the solution. The resulting precipitate was suction filteredand washed with ethyl acetate (10 g) to yield the crude product as ayellow solid.

Isolation and Crystallization of the Free Base:

The crude product (63 g) was dissolved in ethyl acetate (567 g) andmixed with saturated NaHCO₃ solution (126 g). The mixture was stirred at18–25° C. for about 2 h, until no further gas evolution wasascertainable. The aqueous phase was maintained at pH 8–9 with theaddition of more saturated NaHCO₃ solution, as needed. The phases wereseparated and the organic phase was concentrated to about ⅓ volume. Theresulting oil was dissolved in ethyl acetate (100 g) and concentrated todryness. The oil was suspended in acetone (95 g) and heated at reflux(56° C. ±2° C.) for 1 h. The mixture was cooled over 3 h to 36–30° C.,held at this temperature for 2 h, cooled to −10° C. and held at thistemperature for 2 h. The resulting solid was vacuum filtered and washedwith t-butylmethyl ether (10 g). The mother liquor was concentrated,mixed with acetone (41 g), heated to reflux and cooled according to theabove procedure to yield a second crop of product. The solid productsfrom both crops were dried for 1–2 h at 40 deg/50 mbar to yield theproduct as a tan solid.

Yield: 34 g (30–32%)

EXAMPLE 104-(4-fluorophenyl)-2-(4-hydroxy-1-butinyl)-1-(3phenylpropyl)-5-(4-pyridyl)-imidazole

4-(4-Fluorophenyl)-2-bromo-1-(3-phenylpropyl)-5-(4pyridyl)-imidazole(30.19 g) was mixed with diisopropylamine (100.56 g). To the reactionmixture was added 3-butyn-1-ol (5.304 g), dropwise using a syringe.Diisopropylamine (1.810 g) was then added to the reaction mixture towash the syringe, followed by addition of triphenylphosphine (1.805 g),Pd(OAc)₂ (0. 722 g), iron powder (0.384 g), and diisopropylamine (78.64g). The flask was briefly blanketed with nitrogen, then warmed to 70°C., and maintained at this temperature for 3 h.

The above experiment was repeated several times. If the conversion wasdetermined to be less than 95% after three hours, additionaltriphenylphosphine (1.805 g) and palladium acetate (Pd(OAc)₂) (0.772 g)were added and the temperature maintained until conversion of >95% wasachieved.

Upon completion, the reaction mixture was filtered to collect the solidresidue. The filtered residue was suspended with ethyl acetate (212.17g) at 40–50° C., filtered and solvent evaporated to dryness. Theresulting oil was dissolved completely in the first filtrate at 70° C.Water (148.608 g) was added to the hot solution and the phases wereseparated. The organic phase was washed twice with water (148.608 g) at70° C. The phases were separated again and the organic phase washed withbrine (148.608 g) and extracted with 1N HCl (2×146 g). The combined HClphases were re-extracted with ethyl acetate (99.07 g). The water phasewas separated. To the water phase was added 25% ammonia (26.948 g)dropwise, with cooling to 5–10° C. and at a pH 9–10, resulting information of a solid. The suspension was stirred for about 45 min andthe precipitate collected by filtration. The precipitate was slurriedwith water (2×148.61 g) and then dried for 16 h at 40° C./50 mbar. Thesolid was dissolved in a mixture of ethyl acetate (412.21 g) andmethanol (35.270 g), and mixed with Deloxan® (5.00 g). The solution wasstirred for 24 h at 18–23° C. and filtered. The filtered residue waswashed with ethyl acetate (2×15.34 g). The combined mother liquors andwashes were rotoevaporated to dryness. The residue was dissolved in amixture of THF (7.94 g) and toluene (16.0 g) at 70–75° C., cooled slowlyover about 2 h to 18–23° C., resulting in formation of a suspension.Toluene (9.2 g) was then added to the suspension. The suspension solidswere suction filtered, washed with toluene (3×1.40 g), and then washedwith hexane (3×2.02 g). The residue was dried for 16 h at 50° C./50 mbarto yield the product as an off white yellow solid.

Yield: 20.5 g (70.5%)

The above experiment was repeated several times. Recrystallization ofthe above residue as described yielded Form B of the product.Recrystallization of the above residue from acetonitrile, yielded Form Aof the product.

EXAMPLE 11N-(3-phenylpropyl)-N′-[(2,2-dimethoxy-2-(4-pyridyl)-1-(4-flyuorophenyl)ethyl)]urea

To a solution of2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine (1.22 g, 4.4mmol) in THF (10 mL) was added a solution of(3-isocyanatopropyl)-benzene (1.61 g, 10 mmol) in THF (10 mL). Theresulting mixture was stirred at room temperature for 30 minutes. Thereaction was quenched by addition of water (50 mL) and extracted withethyl acetate (2×50 mL). The combined ethyl acetate extract was washedwith water (50 mL), brine (50 mL) and dried with Na₂SO₄. After removalof solvent, the crude product was purified by column chromatography toyield the product as a light brown solid.

Yield: 0.83 g (43%) m.p. 162.5–165.5° C.

EXAMPLE 12 Synthesis of4-(4-fluorophenyl)-2-bromo-1-(3-phenylpropyl)-5-(4-pyridyl)-imidazole

A reaction vessel was charged with POCl₃ (1500.0 g, 9.78 mol). Br₂(184.9 g, 1.157 mol) was then added in one portion at ambienttemperature. The reaction mixture was cooled to 10° C. and then PBr₃(313.0 g, 1,157 mol) was added over 25 min. under vigorous stirring. Thetemperature of the reaction mixture increased to 20° C. After addition,stirring was continued for another 1.5 h, maintaining the temperature inthe range of 10–20° C. The formed PBr₅ precipitated as a yellow solid.The reaction mixture was warmed to 25° C. and1,3-dihydro-1-(3-phenylpropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-imidazol-2-one(150.0 g 0,386 mol) was added in one portion. After addition, thereaction mixture was heated to about 30° C. and stirring was continuedfor 24 h. The suspension changed to a dark solution. The POCl₃ wasdistilled off under vacuum at a temperature below 35° C., to yield aviscous oil. This oil was added to a mixture of ethyl acetate (1000 g)and aqueous ammonia (25 w %, 1000 g) over about 1.25 hours, withcooling. The resulting two phases were separated, the aqueous phase wasextracted with ethyl acetate (500 g) and the combined organic phaseswere washed with water (200 g) at 70° C. The organic phase wasconcentrated to approximately 30% of the original volume. To the warmedreaction mixture, was then added triethylamine (600 g) and an additionalamount of the solvent (about 150 g) was removed in vacuo, resulting inthe crystallization of the desired product. The reaction mixture wascooled to 0° C. and stirred for 12 h. The product was filtered off,washed with triethylamine (50 g) and dried at 40° C. under vacuum, toyield the crude product.

The mother liquor was concentrated to an oil. To the oil was then addedacetone (25 g), resulting in precipitation of the desired product. Theprecipitate was filtered off, washed with acetone (7 g), then withmethyl tert-butylether (8 g) and dried at 40° C. under vacuum to yield asecond crop of the crude product.

Both crops of the isolated product were slurried in a mixture oftriethylamine (10 g) and acetone (100 g), under reflux for 30 min, thencooled to 25° C. and stirred overnight. The precipitate was filteredoff, washed with triethylamine (25 g), then with acetone (10 g) anddried at 40° C. under vacuum to yield the title compound.

HPLC purity: 99%

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for preparing a compound of formula (I)

wherein R¹ is selected from the group consisting of phenyl, substitutedphenyl, (where the substituents are selected from C₁–C₅alkyl, halogen ortrifluoromethyl); R² is a saturated or unsaturated 6 membered ring with5 carbon atoms and one nitrogen atom; R³ is carbocyclic arylC₁–C₅alkyl,wherein the aryl group is optionally substituted with substituentsselected from C₁–C₅alkyl, C₁–C₅alkoxy, halogen, amino, C₁–C₅alkylaminoor di(C₁–C₅alkyl) amino); R⁴ is

 where p is an integer from 0 to 9; X is selected from the groupconsisting of hydrogen, hydroxy, vinyl, substituted vinyl, (where one ormore substituents are selected from fluorine or chlorine), ethynyl,substituted ethynyl (where the substituent is selected from fluorine orchlorine), C₁–C₅alkyl, substituted C₁–C₅alkyl (where the alkylsubstituents are selected from one or more of C₁–C₅alkoxy andtrihaloalkyl,), and C₃–C₇cycloalkyl and pharmaceutically acceptablesalts thereof; comprising

reacting a compound of formula (VIII), wherein L¹ and L² areindependently selected from the group consisting of C₁–C₄alkyl andC₁–C₄aralkyl; or L¹ together with L² is selected from the groupconsisting of —CH₂—CH₂—(optionally substituted with one to four C₁–C₃alkyl), and —CH₂—CH₂—CH₂—(optionally substituted with one to six C₁–C₃alkyl); with a compound of formula (X), to produce the correspondingcompound of formula (XI);

cyclizing the compound of formula (XI), under acid conditions of pH lessthan about 7, to produce the corresponding compound of formula (XII);

reacting the compound of formula (XII) with POBr₃, PBr₅, or a mixture ofPBr₃ and Br₂, to yield the corresponding compound of formula (XIII);

displacing the bromine on the compound of formula (XIII) by reactingwith a compound of formula (XIV), to produce the corresponding compoundof formula (I).
 2. The process of claim 1 wherein R¹ is 4-fluorophenyl,R² is 4-pyridyl, R³ is 3-phenylpropyl and R⁴ is


3. The process of claim 1 wherein the compound of formula (XII) isreacted with POBr₃ in tetramethylenesulfone.